The prognostic value of clinical and pathologic features in nonmetastatic operable male breast cancer

Transcription

1 (2016) 18, AJA, SIMM & SJTU. All rights reserved X Male Health Open Access ORIGINAL ARTICLE The prognostic value of clinical and pathologic features in nonmetastatic operable male breast cancer Bo Sun 1, Li Na Zhang 1, Jun Zhang 1, Ning Zhang 2,3, Lin Gu 1 Compared with female breast cancer, male breast cancer is a rare disease, and the relationship between clinical/pathologic features and prognosis is controversial, or even largely unknown. In this study, we performed a retrospective analysis using clinical and pathologic data from 109 nonmetastatic operable male breast cancer patients treated from January 1996 to December 2011 at Tianjin Medical University Cancer Institute and Hospital. Log rank test showed that lower tumor stage, no lymph node involvement, and positive estrogen/progesterone receptor status were good predictors of both disease free survival and overall survival on univariate analysis. However, hormonotherapy is only a good predictive factor of disease free survival, and not of overall survival. In addition, based on a Cox proportional hazard regression model, only lymph node involvement, and estrogen/progesterone receptor status were statistically significant predictive factors on multivariate analysis. Our results demonstrated that although adjuvant systemic therapy is used extensively in male breast cancer patients and prognosis has improved over the last few decades, lymph node involvement, and estrogen/progesterone receptor status are still the most important prognostic factors. A prospective multi center study with a larger sample size is urgently needed to further understand male breast cancer. (2016) 18, 90 95; doi: / X ; published online: 18 May 2015 Keywords: breast neoplasms; clinical/pathologic features; male; prognosis INTRODUCTION Compared with female breast cancer (FBC), male breast cancer (MBC) is an uncommon disease, accounting for only about 1.0% of all breast carcinomas, and <1.0% of malignant male diseases in the United States. 1,2 Owing to its rarity, our understanding of MBC is not as profound as FBC. 3 Although several studies have included more than 1000 cases, their research is based on the Surveillance Epidemiology and End Results (SEER) database, which only consists of American clinical data. 1,4 However, some reports have shown unique tumor biological behavior among patients from different regions or of different races. 5 7 Therefore, more research regarding MBC patients in China, which accounts for more than 40.0% of the Asian population, is very important for gaining further insight into MBC patients. Another consequence of MBC s rarity is that treatment is largely based on extrapolating results from FBC clinical trials. However, MBC management is challenging because the clinical/pathologic features of MBC are not completely consistent with FBC. 5,8 Therefore, it is necessary to deepen our understanding of MBC to improve patient management. In a previous study, Donegan et al. 9 found that older age at diagnosis and more advanced stage of disease at presentation are related to poorer prognosis of MBC patients in Wisconsin. According to a study including 489 MBC cases in France, T stage and the presence of locoregional recurrence were metastatic risk factors, and axillary nodal involvement and high Scarff, Bloom, and Richardson histoprognostic grading (SBR) were important prognostic factors. 10 In a study undertaken in Turkey, the authors believed that only lymph node status and tumor size were independent prognostic factors for survival. 7 Therefore, there is much controversy regarding the clinical/ pathologic predictive factors for MBC, especially in Chinese patients. In this study, we aimed to evaluate the relationship between clinical/ pathologic features and prognosis in operable Chinese MBC patients. MATERIALS AND METHODS Patients Data for the current study were retrospectively collected from Tianjin Medical University Cancer Institute and Hospital from January 1996 to December The 109 male breast cancer patients included in this study had to fulfill the following criteria: (1) the neoplasms were diagnosed as breast cancer by pathologists using incisional or excisional biopsies; (2) there were no indications that breast cancer cells had spread to other organs or patients had a second cancer at initial diagnosis; (3) all patients underwent curative 1 The Second Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; 2 Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; 3 Laboratory of Translational Cancer Biology, Research Center of Basic Medical Science, Tianjin Medical University, No. 22 Qixiangtai Road, Heping District, Tianjin, China. Correspondence: Dr. L Gu (gulintjmuch@sina.com) Received: 28 October 2014; Revised: 13 January 2015; Accepted: 13 February 2015

2 91 mastectomy surgery; and (4) clinical characteristic and follow up were well documented. Biologic classification Both the estrogen receptor (ER; ZSGB BIO, Beijing, China) and progesterone receptor (PR; ZSGB BIO, Beijing, China) were detected through semi quantitative cell membrane scoring by immunochemistry (IHC). Human epidermal growth factor receptor 2 (HER 2; CerbB 2) status was recognized by IHC (Roche, Mannheim, Germany) and by fluorescent in situ hybridization (FISH; Abbott/ Vysis, Downers Grove, IL, USA). If HER 2 expression was 2+ by IHC, we further analyzed the specimen by FISH. Only FISH positivity was defined as HER 2 expression positive. For all other cases, HER 2 expression was considered negative. Molecular subtype classification was determined as follows: Luminal A, ER positive and/or PR positive and HER2 negative; Luminal B, ER positive and/or PR positive and HER2 positive; HER2 over expression, ER and PR negative and HER2 positive; and Basal like (triple negative), ER, PR and HER2 negative. 11,12 Statistics Data were analyzed using SPSS (17.0; IBM Corp., Armonk, NY, USA). Disease free survival (DFS) and overall survival (OS) were determined by Kaplan Meier survival curve (Log rank). Univariate analysis for DFS and OS were performed with age, histologic type, tumor stage, lymph node involvement, ER/PR status, HER2 status, surgery method, chemotherapy, radiotherapy, and hormonotherapy. Multivariate analysis was performed using a Cox proportional hazard regression model, including interactions between age, tumor stage, lymph node involvement, ER/PR status, HER2 status, chemotherapy, and hormonotherapy. A P < 0.05 was considered as statistically significant. OS was defined as the time from surgery to death by any cause. DFS was defined as the time from surgery to events such as relapse, appearance of a second primary cancer (including contralateral breast recurrence), or death, whichever occurs first. RESULTS Patients characteristics Based on the inclusion criteria, we identified a total 109 patients who had well documented patient data for survival analysis. The number of patients excluded and the reasons for exclusion are shown in Figure 1. Table 1 summarizes the general characteristics of the MBC patients. The mean and median ages at diagnosis were 59.4 and 59 years (range: years), respectively. The mean follow up time was 70.0 months with a range from 10 to 178 months. Left breast carcinomas accounted for the same approximate proportion of MBC as right breast carcinomas (53.2% vs 46.8%). Because of the small breast size, <40.0% of MBC took place in the center of the breast. With respect to MBC clinical and pathologic characteristics, 30.3%, 52.3%, 8.3%, and 10.1% of cases were diagnosed as T 1, T 2, T 3, and T 4, respectively (Table 2). Besides, lymph node involvement was present in 36.7% of MBC patients. In addition, the most common clinical stage was stage II (58.7%) while stages I and III accounted for 19.3% and 22.0%, respectively. In total, 84 (77.1%) patients had invasive ductal carcinoma. Based on the IHC results, ER and PR were positive in 85 (78.0%) and 72 (66.1%) patients, respectively, and HER2 was positive on the basis of FISH results in 20 (18.3%) patients. According to the 2004 St. Gallen consensus, 58, 18, 2 and 8 patients with well documented HER2 status were classified into Luminal A, Luminal B, HER2 overexpression, and triple negative, respectively. Detailed information of treatment modalities is shown in Table 3. Of the 109 MBC patients, 99 (90.8%) underwent radical Table 1: General characteristics of male breast cancer patients Characteristics n (%) Age at diagnosis (year) (0.9) (1.8) (13.8) (39.4) (30.3) >70 15 (13.8) Mean±s.d. 59.4±9.5 Median (range) 59 (26 83) Laterality Left 58 (53.2) Right 51 (46.8) Tumor location Central 42 (38.5) Peripheral quadrant 67 (61.5) Follow up time (month) Mean±s.d. 70.0±34.6 Median (range) 62 (10 178) s.d.: standard deviation Table 2: Clinical and pathologic characteristics of male breast cancer patients Characteristics n (%) Tumor stage T 1 33 (30.3) T 2 57 (52.3) T 3 9 (8.3) T 4 11 (10.1) Lymph node involvement No 69 (63.3) Yes 40 (36.7) AJCC stage I 21 (19.3) II 64 (58.7) III 24 (22.0) Histologic type Invasive ductal carcinoma 84 (77.1) Other types 25 (22.9) ER status Positive 85 (78.0) Negative 19 (17.4) Unknown 5 (4.6) PR status Positive 72 (66.1) Negative 32 (29.4) Unknown 5 (4.6) HER2 status Positive 20 (18.3) Negative 66 (60.6) Unknown 23 (21.1) Molecular subtype Luminal A 58 (53.2) Luminal B 18 (16.5) HER2 overexpression 2 (1.8) Triple negative 8 (7.3) Unknown 23 (21.1) ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; AJCC: american joint committee on cancer

3 92 mastectomy (RM) or modified radical mastectomy (MRM). Owing to different surgical procedures and high risk factors, only 42 (38.5%) patients received radiotherapy for the chest wall or the whole breast as well as for peripheral lymphatics. Typically, the total radiotherapy dose was 50 Gy with a daily fractional dose of 2 Gy. In addition, 92 (84.4%) patients received chemotherapy (details for chemotherapy are shown in Table 4), while 49 patients received hormonotherapy. Figure 1: Flowchart showing the number of patients excluded and the reasons for exclusion. Table 3: Treatment modalities of male breast cancer patients Treatment n (%) Surgery RM or MRM 99 (90.8) Others 10 (9.2) Adjuvant chemotherapy No 17 (15.6) Yes 92 (84.4) TA/TE 28 (25.7) TAC/TEC 13 (11.9) CAF/CEF 21 (19.3) CMF 19 (17.4) Other 11 (10.1) Adjuvant radiotherapy No 67 (61.5) Yes 42 (38.5) Adjuvant hormonotherapy Unknown 5 (4.6) No 55 (50.5) Yes 49 (45.0) Tamoxifen 38 (34.9) Aromatase inhibitor 11 (10.1) RM: radical mastectomy; MRM: modified radical mastectomy Survival analysis Kaplan Meier survival curves (Log rank) were used to calculate DFS and OS; estimated 5 year and 10 year survival rate were 58.7% and 27.7% for DFS, 72.7% and 29.7% for OS, respectively (Figure 2a and 2b). Univariate analysis was performed to reveal the relationship between tumor and treatment related factors on MBC patient survival; patients with smaller tumor stage (T 1 T 2 vs T 3 T 4 ) had better prognosis (DFS and OS, P < 0.05, Figure 3a and 3b). In addition, statistical analysis supported the notion that positive ER/PR status and negative lymph node involvement were associated with a better prognosis (DFS and OS, P < 0.001, Figure 3c 3f). Interestingly, adjuvant hormonotherapy was related to good DFS (P < 0.05), but not OS. However, there is only a slight trend toward decreasing DFS for patients with positive HER2 status (P = 0.09). Table 5 shows further information regarding 5 and 10 year survival rates for DFS and OS by univariate analysis. To further investigate the potential relevance of these factors and patient survival, clinical related factors, including age, tumor stage, lymph node involvement, ER/PR status, HER2 status, chemotherapy, and hormonotherapy, were entered into a Cox proportional hazard regression model (Table 6). The results indicated that only ER/PR status and lymph node involvement were independent factors related to prognosis (ER/PR status: P = and P = for DFS and OS; lymph node involvement: P = and P = for DFS and OS). DISCUSSION Several reports have suggested an alarming increase in MBC incidence over the past few decades. 1,13,14 However, the incidence of MBC in China is still largely unknown. In addition, MBC diagnosis and treatment are still mainly based on the criterion for treating FBC due to MBC exiguity. 1,5 Thus, a better understanding of MBC is urgently needed. In this study, we found the estimated 5 year OS rate at 72.7%, which is higher than previously published data. For instance, according to Foerster et al. 15 study, the 5 year OS is about 68.0% in patients diagnosed with MBC from 1995 to Similarly, Willsher et al. and Marchal et al. showed 5 year OS rates of 55.0% and 58.9%, respectively. 16,17 The fact that our patient OS is above previously reported averages may be attributed to the inclusion of nonmetastatic operable MBC patients involved in this study. In addition, the average age at diagnosis was 59.4 years in our study, which is younger than the average age in other studies, and thus may have contributed to the improved 5 year OS However, owing to the small sample size in our study, there was no significant difference in OS between <60 and 60 groups by univariate analysis (P = 0.120). Tumor stage is a controversial prognosis factor. Some researchers support the opinion that advanced tumor stage is associated with a higher risk of death, while others believe that it is not a pivotal factor. 15,18 In this paper, tumor stage is a prognostic factor for DFS and OS on univariate analysis, but not an independent factor on multivariate analysis. Similarly, lymph node involvement is another focus of debate; Table 4: Chemotherapy details Taxotere Adriamycin Epirubicin Cytoxan Methotrexate 5 FU Days per cycle Cycles TA 75 mg m 2 (day 1) 50 mg m 2 (day 1) 21 6 TE 75 mg m 2 (day 1) 50 mg m 2 (day 1) 21 6 TAC 75 mg m 2 (day 1) 50 mg m 2 (day 1) 500 mg m 2 (day 1) 21 6 TEC 75 mg m 2 (day 1) 50 mg m 2 (day 1) 500 mg m 2 (day 1) 21 6 CAF 50 mg m 2 (day 1) 500 mg m 2 (day 1) 500 mg m 2 (day 1, 8) 21 6 CEF 50 mg m 2 (day 1, 8) 500 mg m 2 (day 1, 8) 400 mg m 2 (day 1, 8) 28 6 CMF 500 mg m 2 (day 1, 8) 40 mg m 2 (day 1, 8) 600 mg m 2 (day 1, 8) 28 6

4 93 a Figure 2: Kaplan Meier curve illustrates prognosis of male breast cancer cases. (a) Disease-free survival of male breast cancer patients. (b) Overall survival of male breast cancer patients. b a b Table 5: Univariate analysis of prognostic factors that may affect the DFS and OS Characteristics n DFS OS Age 5 year 10 year P 5 year 10 year P < Histologic type IDC Other types Tumor stage T 1 T * * T 3 T Lymph node involvement Yes ** ** No ER/PR status Yes ** ** No HER2 status Yes No Surgery RM and MRM Others Adjuvant chemotherapy Yes No Adjuvant radiotherapy Yes No Adjuvant hormonotherapy Yes * No P value was determined by Log rank test. *P<0.05; **P<0.01. DFS: disease free survival; ER: estrogen receptor; HER2: human epidermal growth factor receptor 2; OS: overall survival; IDC: invasive ductal carcinoma; RM: radical mastectomy; MRM: modified radical mastectomy; PR: progesterone receptor Soliman et al. reports that it has a negative effect on OS in a cohort of 69 MBC patients, whereas other authors are in denial. 19,20 In our cohort, lymph node involvement is one of the most important prognosis factors for DFS and OS both on univariate and multivariate analyses. c e Figure 3: Monofactorial analysis of clinical and pathologic factors related to DFS and OS. Comparison of DFS (a) and DFS (b) between T1 T2 and T3 T4 patients. Comparison of DFS (c) and OS (d) between ER/PR negative and positive patients. Comparison of DFS (e) and OS (f) between lymph node negative and positive patients. P value was determined by Log-rank test. DFS: disease-free survival; OS: overall survival; ER: estrogen receptor; PR: progesterone receptor; LN: lymph node. The fact that ER/PR expression in MBC is higher than FBC is less controversial. 4,8 However, how ER/PR status affects MBC prognosis is still unclear owing to possible differences in ER/PR function between males and females. In the present research, 91 patients were ER/PR positive, which accounted for 86.6% of ER/PR status known cases. In addition, ER/PR status was also a predictive factor for DFS and OS both on univariate and multivariate analyses. HER2 overexpression rate is variable in MBC, and ranges from 11.1% to 35.3%. 20,21 In this study, HER2 overexpression accounted for 23.3% of HER2 status known cases, which is consistent with the findings reported by Arslan et al. 18 However, our results demonstrated that HER2 was not a prognosis factor on either univariate or multivariate analyses, which is inconsistent with opinions in FBC. 22 On the basis of ER/PR and HER2 status mentioned above, the proportions of each molecular subtype were distributed as follows: Luminal A, 67.4%; Luminal B, 20.9%; HER2 overexpression, 2.3%; and triple negative, 9.3%. Although Luminal A was the predominate subtype in this cohort, this is not consistent with previous reports, and this phenomenon may be associated with geographical factors. 23 With respect to MBC treatment, people in the north of China preferred RM and MRM over other surgical methods owing to their conservative culture, which is in contrast to patients in other countries. 17,18 Although it has been proven that treatment of FBC d f

5 94 Table 6: Multivariate analysis of prognostic factors that may affect the DFS and OS Characteristics DFS OS Age P Exp(B) 95% CI for Exp(B) P Exp(B) 95% CI for Exp(B) <60 versus Tumor stage T 1 T 2 versus T 3 T Lymph node involvement Yes versus no 0.006** * ER/PR status Positive versus negative 0.048* * HER2 status Positive versus negative Chemotherapy Yes versus no Hormonotherapy Yes versus no P value was determined by a Cox proportional hazard regression model. *P<0.05; **P<0.01. DFS: disease free survival; OS: overall survival; ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor receptor 2; CI: confidence interval can benefit from chemotherapy, radiotherapy, and hormonotherapy, the role of these therapies is less clear in MBC patients. 9,24 26 Our results indicate that chemotherapy and radiotherapy do not affect the prognosis. However, hormonotherapy is a predictor of DFS on monofactorial analysis, but not by Cox regression analysis. However, these outcomes may be a result of the limited sample size or unadjusted clinical/pathologic data. In addition, Trastuzumab is rarely used for Chinese MBC patients because of the low HER2 overexpression rate and exorbitant price. MBC management is based on extrapolation from breast cancer trials in women, yet the issue of different clinical/pathologic prognostic factors and treatments between MBC and FBC is a constant debate. 5,10,13,27 Owing to the relative rarity of MBC, our understanding of this disease is limited on a global level, let alone in China. However, recently, several groups have begun studying MBC patients in China. 20,28 In the present study, limitations such as bias and systemic error were inevitable owing to the small sample size and retrospective study design. Nevertheless, to our knowledge, this is one of few research articles investigating MBC prognosis, including univariate and multivariate analysis with more than 100 cases, in the north of China. Our study corroborates the fact that the ER/PR positivity in MBC is higher than in FBC and supports the notion that ER/PR is a good predictive factor. 5,29 Radiotherapy and hormonotherapy are always a key point of contention in MBC treatment. 29 Our data provide evidence that radiotherapy and hormonotherapy do not have a positive impact on the survival of MBC patients. In addition, through multivariate analysis, this study provides new information that disproves the notion that tumor stage is related to poor survival and confirms that lymph node involvement is a vital predictive factor for prognosis. As a result of low MBC incidence, nearly all data are obtained from retrospective studies to date, and there is only scant research based on prospective studies for evaluating local and systemic treatment modalities. Thus, to better understand MBC, prospective studies with larger sample sizes are necessary. AUTHOR CONTRIBUTIONS LG conceived the idea of the study and participated in its design. BS performed statistical analysis and drafted the manuscript. LNZ and JZ collected the clinical and pathologic data. NZ and LG revised the manuscript. All authors read and approved the final manuscript. COMPETING INTERESTS The authors declare no competing interests. ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China (Grants and ), Tianjin Natural Science fund (Grant 13JCQNJC11000) and Research Seed Foundation of Tianjin Medical University Cancer Hospital and Institute (Grant 1421). REFERENCES 1 Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population based comparison with female breast cancer. J Clin Oncol 2010; 28: Jemal A, Siegel R, Ward E, Hao Y, Xu J, et al. Cancer statistics, CA Cancer J Clin 2008; 58: Agrawal A, Ayantunde AA, Rampaul R, Robertson JF. Male breast cancer: a review of clinical management. Breast Cancer Res Treat 2007; 103: Fields EC, DeWitt P, Fisher CM, Rabinovitch R. Management of male breast cancer in the United States: a surveillance, epidemiology and end results analysis. Int J Radiat Oncol Biol Phys 2013; 87: Giordano SH, Cohen DS, Buzdar AU, Perkins G, Hortobagyi GN. Breast carcinoma in men: a population based study. Cancer 2004; 101: Salehi A, Zeraati H, Mohammad K, Mahmoudi M, Talei AR, et al. Survival of male breast cancer in fars, South of iran. Iran Red Crescent Med J 2011; 13: Selcukbiricik F, Tural D, Aydogan F, Bese N, Büyükünal E, et al. Male breast cancer: 37 year data study at a single experience center in Turkey. J Breast Cancer 2013; 16: Nahleh ZA, Srikantiah R, Safa M, Jazieh AR, Muhleman A, et al. Male breast cancer in the veterans affairs population: a comparative analysis. Cancer 2007; 109: Donegan WL, Redlich PN, Lang PJ, Gall MT. Carcinoma of the breast in males: a multiinstitutional survey. Cancer 1998; 83: Cutuli B, Le Nir CC, Serin D, Kirova Y, Gaci Z, et al. Male breast cancer. Evolution of treatment and prognostic factors. Analysis of 489 cases. Crit Rev Oncol Hematol 2010; 73: Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: Ge Y, Sneige N, Eltorky MA, Wang Z, Lin E, et al. Immunohistochemical characterization of subtypes of male breast carcinoma. Breast Cancer Res 2009; 11: R Giordano SH, Buzdar AU, Hortobagyi GN. Breast cancer in men. Ann Intern Med 2002; 137: Speirs V, Shaaban AM. The rising incidence of male breast cancer. Breast Cancer Res Treat 2009; 115: Foerster R, Foerster FG, Wulff V, Schubotz B, Baaske D, et al. Matched pair analysis

6 95 of patients with female and male breast cancer: a comparative analysis. BMC Cancer 2011; 11: Marchal F, Salou M, Marchal C, Lesur A, Desandes E. Men with breast cancer have same disease specific and event free survival as women. Ann Surg Oncol 2009; 16: Willsher PC, Leach IH, Ellis IO, Bourke JB, Blamey RW, et al. A comparison outcome of male breast cancer with female breast cancer. Am J Surg 1997; 173: Arslan UY, Oksüzoglu B, Ozdemir N, Aksoy S, Alkis N, et al. Outcome of non metastatic male breast cancer: 118 patients. Med Oncol 2012; 29: Soliman AA, Denewer AT, El Sadda W, Abdel Aty AH, Refky B. A retrospective analysis of survival and prognostic factors of male breast cancer from a single center. BMC Cancer 2014; 14: Yu XF, Feng WL, Miao LL, Chen B, Yang HJ. The prognostic significance of molecular subtype for male breast cancer: a 10 year retrospective study. Breast 2013; 22: Rudlowski C, Friedrichs N, Faridi A, Füzesi L, Moll R, et al. Her 2/neu gene amplification and protein expression in primary male breast cancer. Breast Cancer Res Treat 2004; 84: Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER 2/neu oncogene. Science 1987; 235: Sánchez Muñoz A, Román Jobacho A, Pérez Villa L, Sánchez Rovira P, Miramón J, et al. Male breast cancer: immunohistochemical subtypes and clinical outcome characterization. Oncology 2012; 83: Gómez Raposo C, Zambrana Tévar F, Sereno Moyano M, López Gómez M, Casado E. Male breast cancer. Cancer Treat Rev 2010; 36: Cutuli B, Lacroze M, Dilhuydy JM, Velten M, De Lafontan B, et al. Male breast cancer: results of the treatments and prognostic factors in 397 cases. Eur J Cancer 1995; 31A: Giordano SH, Valero V, Buzdar AU, Hortobagyi GN. Efficacy of anastrozole in male breast cancer. Am J Clin Oncol 2002; 25: Pant K, Dutta U. Understanding and management of male breast cancer: a critical review. Med Oncol 2008; 25: Kwong A, Chau WW, Mang OW, Wong CH, Suen DT, et al. Male breast cancer: a population based comparison with female breast cancer in Hong Kong, Southern China: Ann Surg Oncol 2014; 21: Reis LO, Dias FG, Castro MA, Ferreira U. Male breast cancer. Aging Male 2011; 14: